Saturday, April 21, 2018

First FDA Approved Cannabis Product - Epidiolex

Cannabidiol (CBD)

Headlines yesterday were that the FDA Peripheral and Central Nervous System Drugs Advisory Committee approved a cannabis product for the treatment of seizures.  The draft agenda for that meeting is available on the FDA web site but no vote or minutes of the meeting.  This has been a widely hyped application of medical cannabis since the term was first used to try to start the legalization of cannabis products.  Ironically the first example of a patient used as an example for this application did not have the syndrome in question.

At the  time I am typing this post there is no FDA approved package insert for the compound and no prescribing information available on the manufacturer's website.  There is a considerable amount of detail in the patent that is available online.  The patent focuses on the use of cannabidiol in treatment resistant epilepsy including Dravet syndrome; myoclonic absence seizures or febrile infection related epilepsy syndrome (FIRES). The patient states that when  cannabidiol is used for these disorders the total reduction in seizure frequency is 50-70% but as high as 90-100%.  The product is formulated to be used separately or with other anti-epileptic drugs (AED).  The patent suggests that the formulation is comprised of highly purified cannabidiol extract (98% w/w) with most of the psychoactive components - tetrahydrocannabinol (THC) removed.

The epidemiology and treatment of epilepsy especially Dravet's syndrome is reviewed in the patent.  It is clear from that data that there are no good treatments for these disorders and that conventional AEDs are partially effective at best.  The four treatment scenarios (non of which are randomized controlled clinical trials) all demonstrate efficacy for CBD in intractable epilepsy.  These results are included in the table below.

General Response
Best Response
N=27 children and young adults
Dx: severe childhood onset treatment resistant epilepsy (TRE)
Initial dose: CBD 5mg/kg/day titrated to a max of 25 mg/kg/day in addition to baseline AEDs
-after 3 months of therapy, 48% of patients had an equal to or greater than >50% reduction in seizures.
- 2 patients were seizure free at three months
- 6 patients had a 90% reduction in seizures at three months
N=9 children and young adults with treatment-resistant Dravet syndrome
- as above
- after 3 months of therapy, 56% of patients had an equal to or greater than 50% reduction in seizures,
- 2 patient were seizure free at three months
-3 patients has a 90% reduction of seizures at three months
N=4 patients with myoclonic absence seizures who were taking at least two concomitant anti-epileptic drugs
-as above
after 3 months of therapy, 2 of the patients had an equal to or greater than 50% reduction in seizures, 1 patient (25%) had a 90% reduction at the three month stage.
-0 patients were  seizure free
-1 patients with a 90% reduction of seizures at three months
N=3 patients with FIRES (febrile infection related epilepsy syndrome)
-as above
- 2/3 children has a 90% reduction in seizures
-2/3 children had a 90% reduction in seizures and regained some motor and intellectual functioning.

In these studies no patients were withdrawn because of side effects.  Common adverse events were somnolence, fatigue, decreased appetite, increased appetite and diarrhea.  Given the degree of polypharmacy it is probably difficult to determine what side effects are due to CBD and either the other compounds or interactions with the other compounds.   All patients had severe epilepsy with hundreds to thousands of seizures per month and in many cases required episodic aggressive treatment to stop status epilepticus.  In this population, placebo response would be expected to be very low.  The use of CBD in this population could easily be justified on a compassionate use basis because of illness severity and the lack of any severe complications from the CBD.  The results of these open label trials appear to be complied in reference 1.  Some of the authors have also published a review and  randomized, placebo controlled dose ranging study of the safety of CBD.  I cannot imagine that there was not an efficacy arm to that study.  There is also a 2017 commentary that looks at the general question about whether there is adequate evidence that CBD is effective for epilepsy(4).

A mysterious part of the patent process is that this is a simple organic chemistry extraction of CBD from cannabis plants and then resuspending for oral dosing.  The authors specify that THC is essentially removed.  The dosing is done in a standard mg/kg dose that would be expected for any medication. That dose range appears to be part of the patient. Does this patent mean that any CBD extracted from cannabis is the intellectual property of this company or is there more to it than that?  If that is the case then any product with a CBD/THC ratio could be patented and there are currently 11 of these compounds prepared by a similar extraction process in the Minnesota Medical Cannabis Program.  Is each one of these compounds patentable? Or is there some additional information about the formulation that is not included in the patent that would make this formulation more unique? At one point the patent states that the CBD can be synthesized as well as extracted.

The market for this product is potentially significant, if it works in less severe forms of epilepsy. Will it work for example in the case of a person who has a few seizures per month after their AEDs have been optimized?  Can that person take the necessary dose of CBD and not experience significant side effects?  Will the company or other companies try to get another FDA approved indication for CBD related products from the FDA? I suspect the standard will be higher in patients where there are compounds of equal or better efficacy.  Will physicians prescribe CBD derived drugs off-label to people requesting them for philosophical reasons (eg. I want to be treated with a substance derived from a botanical)?  Will the positive effects noted in these small trials persist as more and more people with epilepsy are exposed to the drug?  Will there be more significant side effects with post marketing surveillance and maintenance use? There are still a significant number of people who do not appear to respond very well to CBD.  Those are some of the questions I had considering the implications of this product release.

On theoretical grounds, a key question is whether the utility of this compound in severe epilepsy will lead to additional drug discovery of more compounds for this difficult to treat problem.  For now, the FDA has made a sound decision getting this compound into the hands of the physicians who treat these disorders on a day to day basis.

George Dawson, MD, DFAPA


1:  Devinsky O, Marsh E, Friedman D, Thiele E, Laux L, Sullivan J, Miller I, Flamini R, Wilfong A, Filloux F, Wong M, Tilton N, Bruno P, Bluvstein J, Hedlund J, Kamens R, Maclean J, Nangia S, Singhal NS, Wilson CA, Patel A, Cilio MR. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial. Lancet Neurol. 2016 Mar;15(3):270-8. doi: 10.1016/S1474-4422(15)00379-8. Epub 2015 Dec 24. Erratum in: Lancet Neurol. 2016 Apr;15(4):352. PubMed PMID: 26724101.

2:  O'Connell BK, Gloss D, Devinsky O. Cannabinoids in treatment-resistant epilepsy: A review. Epilepsy Behav. 2017 May;70(Pt B):341-348. doi: 10.1016/j.yebeh.2016.11.012. Epub 2017 Feb 8. Review. PubMed PMID: 28188044.

3: Devinsky O, Patel AD, Thiele EA, Wong MH, Appleton R, Harden CL, Greenwood S, Morrison G, Sommerville K; GWPCARE1 Part A Study Group. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome. Neurology. 2018 Apr 3;90(14):e1204-e1211. doi: 10.1212/WNL.0000000000005254. Epub 2018 Mar 14. PubMedPMID: 29540584

4:  Perucca E. Cannabinoids in the Treatment of Epilepsy: Hard Evidence at Last? J Epilepsy Res. 2017 Dec 31;7(2):61-76. doi: 10.14581/jer.17012. eCollection 2017 Dec. Review. PubMed PMID: 29344464.

5:  FDA Briefing Document Peripheral and Central Nervous System Drugs Advisory Committee Meeting April 19, 2018 NDA 210365Cannabidiol

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